Gene therapy represents a new paradigm of therapy for diseases, where the disease is treated at the molecular level by restoring defective biological functions or reconstituting homeostatic mechanisms within cells. Effective gene therapy requires that the Deoxyribonucleic acid (DNA) successfully accesses the target cell, is taken up for internalisation into the cell, is trafficked through the cell after escaping the degradative pathway to the nucleus, to subsequently be transcribed and translated to produce a desired gene product.
The lung is an important target for gene delivery because aerosol delivery is a non-invasive technique and can directly target the vast surface area of the lung. Plasmid DNA (pDNA) can be introduced into the lung by aerosol inhalation. However, delivery efficiency and durability of the gene vectors to comply with stringent requirements are critical areas for this approach to be successful. Potential obstacles for current pulmonary delivery devices include the retention of the supercoiled structure of the plasmid in the aerosols to retain its transfecting ability and to comply with regulatory requirements on product quality, and to produce aerosol particles with appropriate sizes for optimal delivery to lung surfaces.
Numerous studies have been undertaken in order to determine the feasibility of pulmonary delivery devices in delivering non-complexed pDNA to the lungs. Unfortunately, the supercoiled tertiary structures of pDNA with sizes larger than 5 kilo-base pairs (kbp) have been found to be severely sheared into open circular and fragmented DNA by hydrodynamic shear and shock waves during nebulization in jet and ultrasonic nebulizers. The emergence of new devices such as mesh nebulizers, electrohydrodynamic (EHD) devices and miniaturized nebulization catheter devices have been said to offer greater aerosolization efficiency, and preserve the integrity of pDNA in the aerosols. However, these devices require more clinical studies to demonstrate this.
Inhalation therapy has become the treatment of choice for asthma and chronic obstructive pulmonary disease (COPD). Unlike oral dosing, inhalation therapy allows a high concentration of a drug to be administered and targeted directly to local inflammation sites within the lung, thereby enabling lower total dosages, reduction in systemic side effects, and potentially hastening the onset of action of the drug. Metered Dose Inhalers (MDIs) and Dry Powder Inhalers (DPIs) are commonly used for bronchodilator administration for asthma and COPD therapy; the patient inhales a pre-metered dose in a single forced inspiratory manoeuvre. There is a lively debate among researchers, however, in deciding whether MDIs or DPIs are the most effective or if continuous nebulization to a patient undergoing repeated tidal breathing for a period up to several minutes is required. Though the debate continues, critical factors in making such decisions are generally based on clinical judgements, taking into consideration such factors as dose level, drug efficacy and safety profile, patient age group, disease severity, ease of administration, and cost.
Nebulizers are capable of delivering more drug than current MDIs and DPIs because they operate over a longer period. Moreover, nebulizers do not require coordination skills from the patient, unlike MDIs, and do not require patient actuation via inhalation, unlike DPIs. Nebulizers are commonly used in acute cases of COPD or severe asthma attacks where the patient is unable to self-medicate. For this same reason, nebulizers may be more appropriate for paediatric and geriatric patient populations.
Historically, nebulizers have been large, cumbersome, less portable and more expensive than MDIs or DPIs. Furthermore, conventional nebulizers generally have low dose efficiencies; although more drug may be delivered into an aerosol, much of the aerosolized drug is subsequently wasted because:                1. aerosols are generated continuously, wasting drug as the patient exhales against the nebulizer's output,        2. the aerosols have polydisperse size distributions, with a significant fraction of droplets too large for deep lung deposition, and since        3. nebulizers typically have a large internal residual volume.        
For inhalation therapy to be most effective, the droplet's aerodynamic behaviour (governed by Stokes' law) is of fundamental importance. For deep lung deposition, an aerodynamic diameter less than 5 μm or preferably 3 μm is considered appropriate, such that the aerosol can avoid inertial impaction in the oropharyngeal region. For deposition higher up in the airways, a larger aerodynamic diameter may be preferred. As a result, the aerosol droplet size is crucial to the efficacy of inhalation therapy, and therefore an ideal device capable of efficiently delivering high doses of a drug would permit precise control of the droplet size distribution and preferably offer large atomisation rates to deliver the desired dosage in as short a time period as possible to minimize patient distress and inconvenience.
Nebulization technology has rapidly progressed in recent years, with new methods that utilize ultrasound and electrohydrodynamic atomisation, allowing greater control over the atomisation process to provide aerosols with reduced spreads of polydispersity and with droplet size tuning capability. Furthermore, these methods may be miniaturized, offering an attractive alternative to the large and cumbersome nebulizers that are currently available commercially. Unfortunately, these methods have inherent limitations. For example, electrohydrodynamic atomisation is restricted to high voltage operation—typically several kilovolts—raising safety and reliability issues in consumer use. Various types of ultrasonic atomisation have been devised over the years, and the most common systems use a bath of liquid from which a piezoelectric disc generates an aerosol plume. These ultrasonic nebulizers are also relatively large in size, have limitations on output and size control, and often precipitate the solubilized drug onto the atomisation reservoir walls due to solvent evaporation, wasting the drug and requiring regular cleaning by the user. More recent designs using meshes for nebulization offer better portability, dosage rates, and aerosol monodispersity. The mesh has chemically or laser-cut microscopic holes, forming thousands of orifices that generate droplets under irradiation by ultrasound, although these meshes are prone to clogging, which significantly reduces throughput. In the context of these past and current technologies, a small, portable, reliable, and relatively cost-effective device remains out of reach, especially one that can effectively generate non-agglomerating droplet size distributions which are suitably monodisperse and less than 5-10 μm in diameter.